Trial Information

Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma

OBJECTIVES:

Primary

- Reduce therapy for patients with intermediate-risk neuroblastoma while maintaining a
3-year overall survival (OS) rate of ≥ 95% by using a response-based duration of
therapy algorithm.

- Maintain an overall 3-year OS rate of ≥ 90% for patients within each group.

- Utilize loss of heterozygosity, prospectively, at 1p36 and 11q23 to refine
risk-stratification and treatment assignment, allowing patients whose tumors lack these
chromosomal abnormalities to receive a reduction in therapy, and compare the outcome
with patients treated on COG-A3961.

- Reduce intensity of therapy for patients 365 to < 547 days (12-18 months) of age with
stage 4 neuroblastoma and favorable biological features and maintain a 3-year
event-free survival (EFS) rate consistent with that for patients < 1 year of age with
stage 4 neuroblastoma treated on COG-A3961.

- Reduce intensity of therapy for patients 365 to < 547 days (12-18 months) of age with
stage 3 MYCN-nonamplified but unfavorable histology neuroblastoma and maintain a 3-year
EFS rate consistent with that for patients < 1 year of age with stage 3,
MYCN-nonamplified, unfavorable histology neuroblastoma treated on COG-A3961.

- Reduce surgical morbidity for patients with stage 4S neuroblastoma by allowing for
biopsy only, rather than complete surgical resection, of the primary tumor.

- Systematically study the outcome of patients with stage 4S neuroblastoma who are unable
to undergo biopsy for biology-based risk assignment.

- Determine if the extent of surgical resection correlates with the maintenance of local
control, EFS and/or OS rates, and surgical complication rate.

Secondary

- Determine the results of a standard retrieval approach for patients with residual
disease after 8 courses of initial therapy.

- Determine the results of a standard retrieval approach for patients with progressive,
nonmetastatic disease.

- Identify additional biological surrogate markers for disease relapse and/or metastatic
progression.

- Describe the neurologic outcome of patients with paraspinal neuroblastoma primary
tumors.

- Correlate surgical biopsy technique with adequacy of tissue acquisition for biologic
studies and with complications associated with the biopsy procedure.

- Prospectively validate the prognostic ability of the International Neuroblastoma Risk
Group image-defined risk factor system, and compare the institutional assessment of
image-defined risk factors with that of central review.

OUTLINE: This is a multicenter study. Patients are assigned to 1 of 4 treatment groups by
risk-stratification based on age, stage (INSS stage 2, 3, 4, or 4S), MYCN status (amplified
vs not amplified), histopathologic classification, and tumor DNA index.

- Initial chemotherapy: Courses of initial chemotherapy are administered every 21 days
according to group assignment as outlined below:

- Course 1: Patients receive carboplatin IV over 1 hour on day 1 and etoposide IV
over 1 hour on days 1-3.

- Course 2: Patients receive carboplatin IV over 1 hour, cyclophosphamide IV over 1
hour, and doxorubicin hydrochloride IV over 15 minutes on day 1.

- Course 3: Patients receive cyclophosphamide IV over 1 hour on day 1 and etoposide
IV over 1 hour on days 1-3.

- Course 4: Patients receive carboplatin IV over 1 hour and doxorubicin
hydrochloride IV over 15 minutes on day 1 and etoposide IV over 1 hour on days
1-3.

- Course 5: Patients receive cyclophosphamide IV over 1 hour on day 1 and etoposide
IV over 1 hour on days 1-3.

- Course 6: Patients receive carboplatin IV over 1 hour, cyclophosphamide IV over 1
hour, and doxorubicin hydrochloride IV over 15 minutes on day 1.

- Course 7: Patients receive carboplatin IV over 1 hour on day 1 and etoposide IV
over 1 hour on days 1-3.

- Course 8: Patients receive cyclophosphamide IV over 1 hour and doxorubicin
hydrochloride IV over 15 minutes on day 1.

- Group 1: Patients receive 2 courses of initial chemotherapy. Patients with a
partial response (PR) (50-90% reduction in volume) to chemotherapy proceed to
observation. Patients without a PR receive 2-6 additional courses of
chemotherapy (beginning with course 3). Patients who do not achieve a PR
after additional chemotherapy proceed to retrieval chemotherapy.

- Group 2: Patients receive 4 courses of initial chemotherapy. Patients with a
PR after chemotherapy proceed to observation. Patients without a PR receive
2-4 additional courses of chemotherapy (beginning with course 5). Patients
who do not achieve a PR after additional chemotherapy proceed to retrieval
chemotherapy.

- Group 3: Patients receive 8 courses of initial chemotherapy. Patients under
12 months of age with stage 3, 4, or 4S (not including liver metastases)
disease who achieve a very good PR (VGPR) (> 90% reduction in the volume of
the primary tumor and resolution of metastatic disease) to chemotherapy
proceed to observation. Patients 12-18 months of age with stage 3 or 4
disease who achieve a VGPR proceed to isotretinoin therapy. Patients who do
not achieve a VGPR proceed to retrieval chemotherapy.

- Group 4: Patients receive 8 courses of initial chemotherapy. If a VGPR cannot
be achieved following 8 courses of first-line chemotherapy +/- surgery, then
retrieval chemotherapy with cyclophosphamide/topotecan for 2-6 courses is
administered until a VGPR can be achieved with a combination of chemotherapy
and surgery.

- Retrieval chemotherapy*: Patients receive cyclophosphamide IV over 30 minutes and
topotecan IV over 30 minutes on days 1-5. Treatment repeats every 21 days for up to 6
courses.

- Groups 1 and 2: Patients with a PR after 2-6 courses of retrieval chemotherapy
proceed to observation. Patients without a PR after 2-6 courses of retrieval
chemotherapy are removed from protocol therapy.

- Group 3: Patients under 12 months of age with stage 4 disease with a VGPR after
retrieval chemotherapy proceed to observation. Patients 12-18 months of age with
stage 3 or 4 disease who achieve a VGPR after retrieval chemotherapy proceed to
isotretinoin therapy. Patients who do not achieve a VGPR after retrieval
chemotherapy are removed from protocol therapy.

- Group 4: Group 4 patients who fail to achieve a VGPR or who develop progressive,
non-metastatic disease within 3 years of study enrollment proceed to isotretinoin
therapy. Isotretinoin is also administered to the following Group 4 patients:

- Age 365 to < 547 days at diagnosis, INSS stage 3, MYCN-NA, unfavorable
histology, any ploidy

- Age 365 to < 547 days at diagnosis, INSS stage 4, MYCN-NA, favorable
histology, DI > 1 NOTE: *Patients who have previously received
cyclophosphamide and topotecan to achieve first PR/VGPR are not eligible for
this Retrieval Therapy.

- Surgery: With the exception of patients with INSS 4S disease, patients undergo surgery
to remove as much of the primary tumor and involved lymph nodes as can safely be
accomplished. Reassessment for definitive surgery (for patients who undergo biopsy only
or partial resection at diagnosis) is made at the completion of scheduled chemotherapy
(after course 2 for group 1, after course 4 for group 2, and after course 8 for groups
3 and 4).

- Isotretinoin therapy: Beginning 3-4 weeks after completion of chemotherapy or 2 weeks
post-operatively (for patients who undergo surgical resection), patients receive oral
isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for 6 courses in
the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up periodically for up to 10 years.

Data from patients with low-risk disease who are observed following surgical resection only
and are not enrolled on ANBL0531, are collected for study objectives.